Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a disease characterized by degradation of the anterior horn cells of the spinal cord and has similar characteristics to Spinobulbar muscular atrophy (SBMA). SBMA differs from SMA in its mode of inheritance , the disease-determining gene , the mutational events that trigger disease and the cellular specificity of the disease pathology.
The anterior horn cells control the voluntary muscle contractions from large muscle groups such as the arms and legs. For example, if an individual wants to move his/her arm, electrical impulses are sent from the brain down the anterior horn cells to the muscles of the arm, which then stimulates the arm muscles to contract allowing the arm to move. Degradation is a rapid loss of functional motor neurons. Loss of motor neurons results in progressive symmetrical atrophy of the voluntary muscles. Progressive symmetrical atrophy refers to the loss of function of muscle groups from both sides of the body. For example, both arms and both legs are equally effected to similar degrees of muscle loss and the inability to be controlled and used properly. Progressive loss indicates that muscle loss is not instantaneous, rather, muscle loss occurs consistently over a period of time. These muscle groups include those skeletal muscles that control large muscle groups such as the arms, legs and torso. The weakness in the legs is generally greater than the weakness in the arms.
Spinal muscular atrophy (SMA) arises primarily from degradation of the anterior horn cells of the spinal cord, resulting in proximal weakness and atrophy of voluntary skeletal muscle. Proximal weakness effects the limbs positioned closer to the body, such as arms and legs, rather than more distant body parts such as hands, feet, fingers, or toes.
Spinal muscular atrophy only affects the motor neurons of the spinal cord and voluntary muscles of the limb and trunk. Patients do not display sensory loss, heart problems, or mental retardation. There are numerous secondary complications seen in SMA, including bending of the legs and arms and pneumonia. SMA development involves an initial substantial loss of motor units, followed by a stabilization of the surviving motor units. Motor units refer to an entire motor neuron and the connections within a muscle required for neuronal function.
The childhood form of SMA is subdivided into three main clinical subgroups, Type I, II, and III, depending upon the age of onset and severity. A fourth subgroup, Type O, was recently discovered in London.
Type I SMA, or Werdnig-Hoffmann disease, is the acute or severe form, characterized by severe muscle atrophy. Guido-Werdig, an Austrian doctor, first identified the disease in 1891. He described two brothers displaying progressive muscle weakness from the age of 10 months, starting in the legs and progressing to the back and arms. The first brother died at the age three years with respiratory problems. The second brother survived to the age of six years.
Symptoms emerge in the first three months of life with the affected children never gaining the ability to sit, stand or walk. Swallowing and feeding may be difficult and the child may show difficulties with their own secretions. There is general weakness in the intercostals and accessory respiratory muscles (the muscles situated between the ribs). The chest may appear concave (sunken in) due to the diaphragmatic (tummy) breathing.
Type II SMA was first described in 1964. It is less severe than type I, with clinical symptoms emerging between three and 15 months of age. Most patients can sit but are unable to stand or walk unaided. Feeding and swallowing problems are uncommon in patients with Type II SMA. Again, as with patients diagnosed with type I SMA, the intercostal muscles are affected, with diaphragmatic breathing a main characteristic of children with type II. Most patients will survive beyond the age of four years and, depending upon how their respiratory system is affected, may live through adolescence.
The chronic form of SMA, Type III (Kugelberg-Welander disease) was first described in 1956. The clinical symptoms manifest after the age of four. It produces proximal muscle weakness, predominantly in the lower body. Affected individuals can walk unaided and have a normal life span depending upon the extent of respiratory muscles loss.
Clinicians in London have recently identified a fourth form of the childhood disease; Type 0 SMA. This form appears to have a fetal-onset in that affected individuals display reduced movement within the uterus and are born with severe muscular atrophy with massive motor neuronal cell death. Therefore, these patients have very few functional motor neurons and motor units.
One of the main diagnostic tools is electromyography (EMG). Contraction of voluntary muscle is controlled by electrical impulses originating from the brain. These impulses pass down the motor neurons of the spinal cord to the connecting muscles, where it triggers the contraction. The EMG records this electrical impulse and determines whether the electric current is the same as in normal individuals. Metal needles are inserted into the arms and thigh and the electrical impulse is recorded.
In addition, the speed at which the electric impulse passes down the motor neuron can also be used as a diagnostic test. In SMA patients, both the nerve conduction velocity (NVC) and the EMG readings are reduced.
The third test is an invasive procedure called a muscle biopsy. This involves a surgeon removing a small section of muscle. This is then tested for signs of degradation.
All forms of childhood SMA are autosomal recessive, with both parents needing to be carriers to pass the disease on. If both parents are carriers, there is a 25% chance of their child being affected.
All three forms are caused by a decrease in the production of a protein, termed Survival of Motor Neuron (SMN). The SMN protein is encoded by two nearly identical genes located on chromosome 5; SMN-1 and SMN-2 (previously referred to as telomeric and centomeric SMN, respectively). Remarkably, only mutations or deletions of SMN-1 result in disease development.
In most individuals who do not have SMA, each chromosome (maternal and paternal) contains one copy of SMN-1 and one copy of SMN-2. Therefore, in most unaffected individuals, there are two SMN-1 and two SMN-2 genes. Importantly, a subset of SMA-causing mutations are intragenic SMN-1 single amino acid substitutions. Intragenic indicates that mutations are within an otherwise intact SMN gene, but that there is a small and very subtle mutation that is only found within the SMN gene. This is in contrast to large genomic deletions that can delete the SMN gene and also neighboring genes. The intragenic or small mutations thereby confirms SMN-1 as the SMA-determining gene.
Signs and symptoms
Research shows that, in SMA, the reduced SMN protein levels result in motor neuronal cell degradation. How, and why this occurs is still not known.
Approximately, one in 10,000 live births are affected with SMA, which is slightly lower than expected since the carrier frequency is between one in 40 and one in 50. Since this is a recessive disease, meaning two copies of the abnormal gene must be present for the disease to occur, carriers are unaffected because only one copy of the abnormal gene is present.
The genomic SMN region is remarkably unstable, and de novo mutations (mutations that are new and not inherited from the parents) are quite frequent, accounting for nearly 2% of all SMA cases. In 90% of patients, death occurs before the age of two due to respiratory failure. In North America and Europe, type I SMA accounts for one in every 25,000 infant mortalities. SMA is the leading genetic cause of infantile death and is the second most common autosomal recessive disorder behind cystic fibrosis . Carrier frequencies and disease frequencies are similar throughout the world, although slight variations can exist. Asian populations have a slightly reduced carrier frequency although it is not known why this discrepancy has occurred.
Treatment and management
To date, there is no treatment for childhood SMA. However, there are possible mechanisms through which treatment could be developed. Gene therapy could be used for SMA to replace the abnormal SMN-1 gene. Such treatment is not yet available or possible at this time though.
In Type I SMA, eating and swallowing can become difficult as the muscles of the face are affected. Due to the degradation of the respiratory muscles breathing can also be labored. It is therefore essential for patients to undergo chest physiotherapy (CPT). CPT is a standard set of procedures designed to trigger and aid coughing in patients. Coughing is important as it clears the patients lungs and throat of moisture and prevents secondary problems, such as pneumonia.
As symptoms progress, patients may require a ventilator to aid breathing. There are two main forms of ventilation systems. Negative Pressure Ventilation can be achieved by placing the patient in a Port-A-Lung. This machine ensures that the air pressure around the patient is lower than the air pressure within the patient's lungs, enabling easier breathing. The pressure can be raised or lowered if the patients ventilation rate increases or decreases.
The second method is called Bi-Pap (Biphasic Positive Airway Pressure). This procedure involves the insertion of a small tube down the nose into the patient's lungs, through which oxygen is pumped into the lungs and waste carbon dioxide is removed. This system allows maximum inspiration and expiration levels to be reached.
Of all the forms of childhood SMA, Type II is the most diverse. It is therefore hard to tell when muscle weakness will occur and how severe the disease will be. With the aid of leg braces and walking devices, some children may gain the ability to stand. Unlike Type I SMA, not all children with Type II are affected by respiratory weakness. The main cause of death in patients with Type II is respiratory failure resulting from a respiratory infection. It is therefore important to ensure that mucus does not build up in patients respiratory tracts as this could aid viral and bacterial infections.
Crawford, T. O., and C. A. Pardo. "The neurobiology of childhood spinal muscular atrophy." Neurobiology of Disease 3 (1996): 97-110.
Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.
Families of Spinal Muscular Atrophy. <http://www.fsma.org>.
The Andrew's Buddies web site. FightSMA.com <http://www.andrewsbuddies.com/news.html>.
Philip J. Young
Christian L. Lorson, PhD
Spinal Muscular Atrophy
Spinal muscular atrophies (SMAs) are a wide group of genetic disorders characterized by primary degeneration of anterior horn cells of the spinal cord, resulting in progressive muscle weakness. The most common form of spinal muscular atrophy is childhood proximal SMA. Other forms of SMAs include X-linked recessively inherited bulbospinal SMA, distal SMAs, scapuloperoneal SMAs, and others such as facioscapulohumeral, scapulohumeral, oculopharyngeal, and Ryukyuan SMAs.
SMAs present with diverse symptoms and differ in age of onset, mode of inheritance, distribution of muscle weakness, and progression of symptoms.
Childhood proximal SMA is subdivided into three clinical groups: type I, type II, and type III SMA. SMA type IV designates adult form of proximal SMA. Although it is now apparent that the phenotype of SMA associated with mutations of the survival motor neuron (SMN1) gene spans a continuum without a clear delineation of subtypes, the classification is useful for prognosis and management.
SMA I (acute infantile SMA, Werdnig-Hoffman disease) manifests by decreased fetal movements in the last trimester of pregnancy in about one third of cases. About 65% of affected infants are floppy at birth, while delayed motor milestones are characteristic in all affected children by the age of six months. In addition to muscle weakness, clinical features include head lag, poor sucking and swallowing, weak cry, proximal limb weakness, and lack of reflexes. Affected children never raise their head, roll over, or walk. Sometimes weakness of the face and jaw muscles, finger tremor, and respiratory difficulty occur. Orthopedic abnormalities such as congenital dislocation of the hip, chest wall asymmetries, and flexion contractures are present in 25% of affected newborns.
SMA II (intermediate SMA) usually manifests itself between six and 12 months of age. Although poor muscle tone may be evident at birth or within the first few months of life, patients with SMA II may gain motor milestones slowly. Eighty percent are able to sit independently, although they are not able stand or walk alone. Limb girdle weakness, twitching, lack of reflexes, and weakness of tongue, face, and neck muscles are seen. Tremors affecting the upper extremities, musculoskeletal deformities, and respiratory failure occur.
SMA III (chronic SMA, Kugelberg-Welander disease) presents with the onset of symptoms after the age of 18 months. Patients walk independently, but may fall frequently or have trouble walking up and down stairs between age two to three years. Muscular weakness is present on both sides of the body, and the legs are more severely affected than the arms. Difficulty swallowing and difficulty speaking may occur in later stages of the disorder.
SMA IV manifests as muscle weakness usually in the second or third decade of life. The findings are similar to those described for SMA III.
Bulbospinal muscular atrophy (Kennedy disease) manifests as muscle weakness between the ages of 20 and 40 years. Weakness and atrophy in the lower extremities are usually followed by problems with the pectoral girdle, facial muscles, distal limb, and bulbar muscles. Muscle cramps on exertion often precede the weakness by several years. Fine tremors of the face are present in over 90% of patients. Type 2 diabetes mellitus, hand tremor, and infertility can also occur. Bulbar involvement predisposes the person with spinal muscular atrophy to recurrent aspiration pneumonia, due to weakening of the muscles necessary for efficient swallowing.
Other less common forms of SMAs include distal SMAs (10% of all SMA cases) and scapuloperoneal SMA (7% of all SMA cases). Distal SMAs are a group of disorders that manifest most commonly soon after birth, with muscle wasting in the hands and feet. Later in life, abnormal gait and foot deformities are seen. Similar clinical signs occur in adult-onset forms. Scapuloperoneal SMA has a characteristic pattern of muscle weakness, usually involving the heart and sensory neuropathy (Davidenkow's syndrome).
SMAs are one of the most common groups of neuromuscular diseases in children, with an incidence of four to 10 per 100,000 live births. Other SMAs have a lower incidence, as a rule less than one per 100,000 live births.
Causes and symptoms
Spinal muscular atrophies are genetic diseases. Types I, II, and III SMAs have been mapped to chromosome 5q11.2-13.3. In 1994, the survival motor neuron (SMN1) gene was identified as responsible for SMA when mutations occur. The SMN1 gene has a duplicate copy called the SMN2 gene, but it is not able to compensate for the defects in the SMN1 gene. There is evidence that type I SMA is caused by deletion of the SMN1 gene, whereas type III is associated with a conversion event of SMN1 into SMN2, leading to an increased number of SMN2 genes. In addition to bulbospinal muscular atrophy, which has been shown to be caused by a defect in the androgen receptor gene, six other SMAs have already been mapped to corresponding chromosomal locations.
Inheritance pattern for most forms of SMA is autosomal recessive, meaning that both parents are carriers of the disorder, and the chance of having a child affected with the disorder is 25% with each pregnancy. Familial forms of the disorder that occur later in life are usually due to an autosomal recessive or autosomal dominant inheritance pattern.
Diagnosis is based on the clinical presentation, family history, and genetic testing. The genetic test is based on the fact that approximately 95–98% of individuals with a clinical diagnosis of childhood SMA lack exon 7 in both copies of the SMN1 gene. Likewise, all patients with bulbospinal muscular atrophy have a defect in the androgen receptor gene.
An electromyelogram may reveal damaged nerve impulses secondary to muscle fiber degeneration. Sensory nerve conduction studies are normal in all forms of SMA, the exceptions being bulbospinal muscular atrophy and Davidenkow's syndrome. Muscle biopsy is critical in the diagnosis of childhood SMA. If performed, it reveals atrophy of muscle fibers with a characteristic form of muscle fiber type grouping.
A multidisciplinary approach is essential for providing care and treatment of a person with spinal muscular atrophy, including specialists in the fields of neurology, physical therapy, occupational therapy, respiratory therapy, surgery, and genetic counseling.
As no specific treatment is available for spinal muscular atrophies, the resulting complications of muscle deterioration are managed as best as possible. Treatment in severe childhood SMA includes prescription of antibiotics for respiratory infections and tube feeding in children with profound difficulty in sucking and swallowing. In children with SMA II, the goals of conservative therapy include maintaining the sitting posture, preserving or improving function, and reducing progression of deformity. This is achieved by regular active exercise monitored by physical therapists, gentle traction to prevent contractures (stiff muscles near the joints), splinting, bracing, and the use of spinal positioning devices and upright mobility systems. Orthopedic surgical interventions such as tendon transfer or spinal surgery can prevent disability in patients with expected prolonged survival.
Recovery and rehabilitation
As there is no recovery from spinal muscular atrophies, the emphasis is placed upon maintaining muscle function and mobility for as long as possible. Physical therapy is an integral part of maintaining movement in persons with spinal muscular atrophies. In children, range of motion exercises keep muscles and joints moving, while reaching games provide stimulation and aid in coordination. Water therapy also provides an enjoyable medium for working the muscles and joints.
As muscle weakness progresses and affects posture, occupational therapy can provide assistive devices and strategies to maintain positioning and movement, such as specialized wheelchairs and reaching devices. Respiratory therapy is also important to teach parents the chest therapy exercises and maneuvers that are necessary to remove accumulated secretions and mucous from the lungs.
Normal education should be encouraged for children with spinal muscular atrophies, especially in the more slowly progressive forms, as intelligence is preserved and even superior in many children with SMA.
Riluzole, gabapentin , albuterol, phenylbutyrate, and thyrotropin-releasing hormone have so far been tested and have shown potential effects on improvement of muscle strength in children with SMA. Many different controlled trials are needed to confirm these preliminary findings.
Progressive muscle weakness usually leads to death by age four for persons with SMA I. Muscle weakness progresses at varying rates in SMA II, and many persons survive into adulthood. The life expectancy of patients with SMA III is close to that of the healthy population. Progression of the adult-onset SMAs is usually slow, and patients are ambulatory until late in the disease. Lifespan is only slightly reduced.
Genetic counseling is important in SMA, since prenatal and preimplantation genetic diagnoses offer the parents the possibility to prevent the disease.
"Disorders of Upper and Lower Motor Neurons," chapter 80 in Neurology in Clinical Practice, edited by Walter G. Bradley, Robert B. Daroff, Gerald Fenichel, and Joseph Jankovic. Burlington, MA: Butterworth Heinemann, 2003.
Zerres, K., S. Rudnik-Schoneborn, E. Forrest, et al. "A Collaborative Study on the Natural History of Childhood and Juvenile Onset Proximal Spinal Muscular Atrophy (Type II and III SMA): 569 Patients." J Neurol Sci. 146 (February 1997): 67–72.
"NINDS Spinal Muscular Atrophy Information Page." National Institute of Neurological Disorders and Stroke. May 5, 2004 (May 27, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/sma.htm>.
"Understanding Spinal Muscular Atrophy: A Comprehensive Guide." Families of Spinal Muscular Atrophy. May 5, 2004 (May 27, 2004). <http://www.fsma.org/booklet.shtml#taking>.
Borut Peterlin, MD, PhD
Spinal Muscular Atrophy
Spinal muscular atrophy is a term that describes a number of different conditions, all of which have in common the gradual deterioration of the voluntary muscles.
Several different conditions fall under the name spinal muscular atrophy (SMA). These include SMA type I, also called Werdnig-Hoffmann; SMA type II; SMA type III, also called Kugelberg-Welander disease; Kennedy syndrome, or progressive spinobulbar muscular atrophy; and congenital SMA with arthrogryposis.
The autosomal recessive forms of spinal muscular atrophy are the most common inherited cause of infant death. Each type of spinal muscular atrophy has an incidence of about 10 to 15 cases in every 100,000 live births.
Causes and symptoms
All types of spinal muscular atrophy are genetic diseases. Most of the syndromes are autosomal recessive, meaning that they have no predilection for either sex. Parents of children with SMA usually carry the gene for the disease but have no symptoms themselves. A child who receives two genes (one from each parent) will express the symptoms of the disease.
Although the entire sequence of abnormalities that causes spinal muscular atrophy was not delineated as of 2004, there is thought to be an absence or deficiency of a specific protein necessary for the proper functioning of the nerve cells responsible for movement (motor neurons).
SMA type I (Werdnig-Hoffmann disease)
SMA type I is usually noted prior to birth, due to a decrease in the baby's movements in utero, or early in life. Babies with this type of SMA have decreased muscle and trunk tone, resulting in floppiness of the limbs and weak arm and leg movements. They have difficulty with swallowing and, therefore, with feeding, and they have breathing problems. These children are unable to learn to sit or to stand. The disease is usually fatal prior to the age of two.
SMA type II
Symptoms of SMA type II are usually noted in a child between three and 15 months of age. Symptoms include breathing problems; weak and floppy limbs; involuntary jerking and twitching of muscles in the arms, legs, and tongue; abnormal reflexes. Children with SMA type II may eventually be able to sit, but they are unable to learn to stand or to walk.
SMA type III (Kugelberg-Welander disease)
Children with SMA type III begin to experience symptoms between the ages of two and 17 years. Problems develop that hamper the child's ability to walk, run, climb stairs, and rise from a chair. Twitches and tremors may develop in the child's fingers.
Kennedy syndrome (progressive spinobulbar muscular atrophy)
This form of spinal muscular atrophy only affects men; it is an X-linked recessive disorder, meaning that the defective gene is passed from mother to son. Individuals with Kennedy syndrome begin to develop symptoms between the ages of 15 and 60 years. Characteristic symptoms include increasing weakness of the tongue and facial muscles, problems with swallowing, impaired speech, and increased size of the male breast (gynecomastia). The severity of the symptoms of Kennedy syndrome progress gradually.
Congenital SMA with arthrogryposis
This is one of the rarest forms of spinal muscular atrophy. It is present at birth, and children exhibit severe contractures of the joints, resulting in limb deformity; spinal curvature; deformities of the chest wall; difficulties breathing; abnormally small jaw; and upper eyelid droop (ptosis).
Diagnosis is by a combination of clinical observation; blood tests that reveal an increased level of creatine kinase (which appears in the blood when muscle tissue is being broken down); distinctive abnormalities on muscle biopsy; characteristic electromyographic and nerve conduction abnormalities; and genetic testing.
There are no cures for any of the forms of spinal muscular atrophy. The treatments involve addressing the symptoms and attempting to improve quality of life. Medical treatment may be necessary for recurrent pneumonia and other respiratory infections. Surgery may be necessary for spinal curvature and severe contractures. Physical therapy, occupational therapy, and other types of rehabilitation programs may help individuals achieve the highest level of functioning possible.
The prognosis for spinal muscular atrophy is variable. Life expectancy is dependent on the degree of respiratory impairment present. Because of the slow progression of symptoms, individuals with Types III or Kennedy syndrome may have normal life spans.
There is no way to prevent spinal muscular atrophy. However, genetic counseling is crucial so that parents can make informed decisions about having children. In general, when a family has already had a child with SMA, each subsequent pregnancy has a 25 percent chance of producing another child with SMA. Prenatal testing is available. Parents must then decide whether to use the information to help them prepare for the arrival of a baby with SMA or to terminate the pregnancy.
Caring for a child with SMA can be very challenging and emotionally draining. Support groups, respite care, and help to support other siblings in the family can be important adjunct measures.
"Disorders of Neuromuscular Transmission and of Motor Neurons." In Nelson Textbook of Pediatrics. Edited by Richard E. Behrman et al. Philadelphia: Saunders, 2004.
Siddique, Nailah. "Degenerative Motor, Sensory, and Autonomic Disorders." In Textbook of Clinical Neurology. Edited by Christopher G. Goetz. Philadelphia: Saunders, 2003.
Muscular Dystrophy Association—USA. 3300 E. Sunrise Drive, Tucson, AZ 85718. Web site: <www.mdausa.org>.
NIH Neurological Institute., PO Box 5801, Bethesda, MD 20824. Web site: <www.ninds.nih.gov>.
Rosalyn Carson-DeWitt, MD